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Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling

Nature Immunology volume 4, pages 1057–1064 (2003)Cite this article

Abstract

Lymphocyte antigen receptors are responsible for inducing the opposite responses of immunity or tolerance. How the correct polarity of antigen receptor signaling is encoded has been an enduring enigma. Here we summarize recent advances defining key scaffolding molecules, CARMA1 (also known as CARD11) and the Cbl family of ubiquitin ligases, required for either immunogenic or tolerogenic signaling by antigen receptors. These scaffolding proteins may determine the polarity of response to antigen by promoting assembly around antigen receptors of competing multiprotein signal complexes: immunosomes versus tolerosomes. Each of the factors that influence immunogenicity or tolerogenicity—stage of lymphocyte differentiation, concurrent engagement of inhibitory or costimulatory receptors, extent of receptor crosslinking, and prior antigen experience—may be integrated in lymphocytes through their capacity to influence the probability of assembling immunosomes versus tolerosomes.

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Figure 1: BCR and TCR early signalosomes are essential for triggering an increase in calcium.
Figure 2: Multiprotein interactions are scaffolded by membrane-associated guanylate kinase family proteins.
Figure 3: Hypothesized mechanism for the generation of immunogenic signals by receptor multimerization, costimulatory receptors and CARMA1.
Figure 4: Hypothesized function of Cbl family proteins to assemble tolerogenic signalosomes.

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References

  1. Burnet, F.M. The Clonal Selection Theory of Acquired Immunity (Vanderbilt University Press, Nashville, 1959).

    Google Scholar 

  2. Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

    CAS  PubMed  Google Scholar 

  3. Burnet, F.M., Stone, J.D. & Edney, M. The failure of antibody production in the chick embryo. Aust. J. Exp. Biol. Med. Sci. 28, 291–297 (1950).

    CAS  PubMed  Google Scholar 

  4. Nossal, G.J.V. The immunological response of foetal mice to influenza virus. Austral. J. Exp. Biol. 35, 549–558 (1957).

    CAS  PubMed  Google Scholar 

  5. Buchmeier, M.J., Welsh, R.M., Dutko, F.J. & Oldstone, M.B. The virology and immunobiology of lymphocytic choriomeningitis virus infection. Adv. Immunol. 30, 275–331 (1980).

    CAS  PubMed  Google Scholar 

  6. Goodnow, C.C. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc. Natl. Acad. Sci. USA 93, 2264–2271 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Burnet, F.M. & Fenner, F. The Production of Antibodies (Macmillan, Melbourne, 1949).

    Google Scholar 

  8. Baxter, A.G. & Hodgkin, P.D. Activation rules: the two-signal theories of immune activation. Nat. Rev. Immunol. 2, 439–446 (2002).

    CAS  PubMed  Google Scholar 

  9. Dintzis, H.M., Dintzis, R.Z. & Vogelstein, B. Molecular determinants of immunogenicity: the immunon model of immune response. Proc. Natl. Acad. Sci USA 73, 3671–3675 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dresser, D.W. & Mitchison, N.A. The mechanism of immunological paralysis. Adv. Immunol. 8, 129–181 (1968).

    CAS  PubMed  Google Scholar 

  11. Grossman, Z. & Paul, W.E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc. Natl. Acad. Sci. USA 89, 10365–10369 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sheng, M. & Sala, C. PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, 1–29 (2001).

    CAS  PubMed  Google Scholar 

  13. Fanning, A.S. & Anderson, J.M. Protein modules as organizers of membrane structure. Curr. Opin. Cell Biol. 11, 432–439 (1999).

    CAS  PubMed  Google Scholar 

  14. Crabtree, G.R. Calcium, calcineurin, and the control of transcription. J. Biol. Chem. 276, 2313–2316 (2001).

    CAS  PubMed  Google Scholar 

  15. Healy, J.I. et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6, 419–428 (1997).

    CAS  PubMed  Google Scholar 

  16. Dolmetsch, R.E., Lewis, R.S., Goodnow, C.C. & Healy, J.I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).

    CAS  PubMed  Google Scholar 

  17. Frantz, B. et al. Calcineurin acts in synergy with PMA to inactivate IκB/MAD3, an inhibitor of NF-kappa B. EMBO J 13, 861–870 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gerondakis, S., Grossmann, M., Nakamura, Y., Pohl, T. & Grumont, R. Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts. Oncogene 18, 6888–6895 (1999).

    CAS  PubMed  Google Scholar 

  19. Peng, S.L., Gerth, A.J., Ranger, A.M. & Glimcher, L.H. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14, 13–20 (2001).

    CAS  PubMed  Google Scholar 

  20. Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002).

    CAS  PubMed  Google Scholar 

  21. Glynne, R. et al. How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis. Nature 403, 672–676 (2000).

    CAS  PubMed  Google Scholar 

  22. Youn, H.D., Sun, L., Prywes, R. & Liu, J.O. Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science 286, 790–793 (1999).

    CAS  PubMed  Google Scholar 

  23. Calnan, B.J., Szychowski, S., Chan, F.K., Cado, D. & Winoto, A. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3, 273–282 (1995).

    CAS  PubMed  Google Scholar 

  24. Jordan, M.S., Singer, A.L. & Koretzky, G.A. Adaptors as central mediators of signal transduction in immune cells. Nat. Immunol. 4, 110–116 (2003).

    CAS  PubMed  Google Scholar 

  25. Fruman, D.A., Satterthwaite, A.B. & Witte, O.N. Xid-like phenotypes: a B cell signalosome takes shape. Immunity 13, 1–3 (2000).

    CAS  PubMed  Google Scholar 

  26. Werlen, G. & Palmer, E. The T-cell receptor signalosome: a dynamic structure with expanding complexity. Curr. Opin. Immunol. 14, 299–305 (2002).

    CAS  PubMed  Google Scholar 

  27. Kurosaki, T. Regulation of B-cell signal transduction by adaptor proteins. Nat. Rev. Immunol. 2, 354–363 (2002).

    CAS  PubMed  Google Scholar 

  28. Samelson, L.E. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu. Rev. Immunol. 20, 371–394 (2002).

    CAS  PubMed  Google Scholar 

  29. Janssen, E., Zhu, M., Zhang, W. & Koonpaew, S. LAB: a new membrane-associated adaptor molecule in B cell activation. Nat. Immunol. 4, 117–123 (2003).

    CAS  PubMed  Google Scholar 

  30. Brdicka, T. et al. Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling. J. Exp. Med. 196, 1617–1626 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Weiss, A. & Schlessinger, J. Switching signals on or off by receptor dimerization. Cell 94, 277–280 (1998).

    CAS  PubMed  Google Scholar 

  32. El-Hillal, O., Kurosaki, T., Yamamura, H., Kinet, J.P. & Scharenberg, A.M. syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction. Proc. Natl. Acad. Sci. USA 94, 1919–1924 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rolli, V. et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol. Cell 10, 1057–1069 (2002).

    CAS  PubMed  Google Scholar 

  34. Reth, M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat. Immunol. 3, 1129–1134 (2002).

    CAS  PubMed  Google Scholar 

  35. Dykstra, M., Cherukuri, A., Sohn, H.W., Tzeng, S.J. & Pierce, S.K. Location is everything: lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21, 457–481 (2003).

    CAS  PubMed  Google Scholar 

  36. Awasthi-Kalia, M., Schnetkamp, P.P. & Deans, J.P. Differential effects of filipin and methyl-beta-cyclodextrin on B cell receptor signaling. Biochem. Biophys. Res. Commun. 287, 77–82 (2001).

    CAS  PubMed  Google Scholar 

  37. Kabouridis, P.S., Janzen, J., Magee, A.L. & Ley, S.C. Cholesterol depletion disrupts lipid rafts and modulates the activity of multiple signaling pathways in T lymphocytes. Eur. J. Immunol. 30, 954–963 (2000).

    CAS  PubMed  Google Scholar 

  38. Pizzo, P. & Viola, A. Lymphocyte lipid rafts: structure and function. Curr. Opin. Immunol. 15, 255–260 (2003).

    CAS  PubMed  Google Scholar 

  39. Horejsi, V. Membrane rafts in immunoreceptor signaling: new doubts, new proofs? Trends Immunol. 23, 562–564 (2002).

    CAS  PubMed  Google Scholar 

  40. Koyasu, S. The role of PI3K in immune cells. Nat. Immunol. 4, 313–319 (2003).

    CAS  PubMed  Google Scholar 

  41. Turner, M. & Billadeau, D.D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat. Rev. Immunol. 2, 476–486 (2002).

    CAS  PubMed  Google Scholar 

  42. Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995).

    CAS  PubMed  Google Scholar 

  43. Sommers, C.L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040–2043 (2002).

    CAS  PubMed  Google Scholar 

  44. Li, Q. & Verma, I.M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).

    CAS  PubMed  Google Scholar 

  45. Schwartz, R.H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2002).

    Google Scholar 

  46. Mondino, A. et al. Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells. J. Immunol. 157, 2048–2057 (1996).

    CAS  PubMed  Google Scholar 

  47. Sundstedt, A. et al. In vivo anergized CD4+ T cells express perturbed AP-1 and NF-κB transcription factors. Proc. Natl. Acad. Sci. USA 93, 979–984 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kane, L.P., Lin, J. & Weiss, A. It's all Rel-ative: NF-κB and CD28 costimulation of T-cell activation. Trends Immunol. 23, 413–420 (2002).

    CAS  PubMed  Google Scholar 

  49. Dong, C., Davis, R.J. & Flavell, R.A. MAP kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    CAS  PubMed  Google Scholar 

  50. Golub, E.S. & Weigle, W.O. Studies on the induction of immunologic unresponsiveness. I. Effects of endotoxin and phytochemagglutinin. J. Immunol. 98, 1241–1247 (1967).

    CAS  PubMed  Google Scholar 

  51. Hartley, S.B. et al. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72, 325–335 (1993).

    CAS  PubMed  Google Scholar 

  52. Tsubata, T., Wu, J. & Honjo, T. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature 364, 645–648 (1993).

    CAS  PubMed  Google Scholar 

  53. Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nat. Immunol. 3, 830–835 (2002).

    CAS  PubMed  Google Scholar 

  54. Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation. Nat. Immunol. 3, 836–843 (2002).

    CAS  PubMed  Google Scholar 

  55. Pomerantz, J.L., Denny, E.M. & Baltimore, D. CARD11 mediates factor-specific activation of NF-κB by the T cell receptor complex. EMBO J. 21, 5184–5194 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hara, H. et al. The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 18, 763–775 (2003).

    CAS  PubMed  Google Scholar 

  57. Newton, K. & Dixit, V.M. Mice Lacking the CARD of CARMA1 exhibit defective B lymphocyte development and impaired proliferation of their B and T lymphocytes. Curr. Biol. 13, 1247–1251 (2003).

    CAS  PubMed  Google Scholar 

  58. Egawa, T. et al. Requirement for CARMA1 in antigen receptor-induced NF-κB Activation and lymphocyte proliferation. Curr. Biol. 13, 1252–1258 (2003).

    CAS  PubMed  Google Scholar 

  59. Jun, J.E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003).

    CAS  PubMed  Google Scholar 

  60. Dimitratos, S.D., Woods, D.F., Stathakis, D.G. & Bryant, P.J. Signaling pathways are focused at specialized regions of the plasma membrane by scaffolding proteins of the MAGUK family. Bioessays 21, 912–921 (1999).

    CAS  PubMed  Google Scholar 

  61. Mercurio, F. et al. IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-kappaB activation. Science 278, 860–866 (1997).

    CAS  PubMed  Google Scholar 

  62. Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. & Goeddel, D.V. IκB kinase-β: NF-κB activation and complex formation with IκB kinase-α and NIK. Science 278, 866–869 (1997).

    CAS  PubMed  Google Scholar 

  63. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

    CAS  PubMed  Google Scholar 

  64. Bertin, J. et al. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-κB. J. Biol. Chem. 276, 11877–11882 (2001).

    CAS  PubMed  Google Scholar 

  65. Gaide, O. et al. Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-κB activation. FEBS Lett. 496, 121–127 (2001).

    CAS  PubMed  Google Scholar 

  66. Su, T.T. et al. PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nat. Immunol. 3, 780–786 (2002).

    CAS  PubMed  Google Scholar 

  67. Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).

    CAS  PubMed  Google Scholar 

  68. Saijo, K. et al. Protein kinase C β controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195, 1647–1652 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13, 463–473 (2000).

    CAS  PubMed  Google Scholar 

  70. Irvine, D.J., Purbhoo, M.A., Krogsgaard, M. & Davis, M.M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

    CAS  PubMed  Google Scholar 

  71. Symer, D.E., Dintzis, R.Z., Diamond, D.J. & Dintzis, H.M. Inhibition or activation of human T cell receptor transfectants is controlled by defined, soluble antigen arrays. J. Exp. Med. 176, 1421–1430 (1992).

    CAS  PubMed  Google Scholar 

  72. Wulfing, C. & Davis, M.M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266–2269 (1998).

    CAS  PubMed  Google Scholar 

  73. Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999).

    CAS  PubMed  Google Scholar 

  74. Brunswick, M. et al. Surface immunoglobulin-mediated B-cell activation in the absence of detectable elevations in intracellular ionized calcium: a model for T-cell-independent B-cell activation. Proc. Natl. Acad. Sci. USA 86, 6724–6728 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sanui, T. et al. DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T Cells. Immunity 19, 119–129 (2003).

    CAS  PubMed  Google Scholar 

  76. Gajewski, T.F., Qian, D., Fields, P. & Fitch, F.W. Anergic T-lymphocyte clones have altered inositol phosphate, calcium, and tyrosine kinase signaling pathways. Proc. Natl. Acad. Sci. USA 91, 38–42 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. LaSalle, J.M., Tolentino, P.J., Freeman, G.J., Nadler, L.M. & Hafler, D.A. Early signaling defects in human T cells anergized by T cell presentation of autoantigen. J. Exp. Med. 176, 177–186 (1992).

    CAS  PubMed  Google Scholar 

  78. Jenkins, M.K., Pardoll, D.M., Mizuguchi, J., Chused, T.M. & Schwartz, R.H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc. Natl. Acad. Sci. USA 84, 5409–5413 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kimura, M. et al. Impaired Ca/calcineurin pathway in in vivo anergized CD4 T cells. Int. Immunol. 12, 817–824 (2000).

    CAS  PubMed  Google Scholar 

  80. Asai, K. et al. T cell hyporesponsiveness induced by oral administration of ovalbumin is associated with impaired NFAT nuclear translocation and p27kip1 degradation. J. Immunol. 169, 4723–4731 (2002).

    CAS  PubMed  Google Scholar 

  81. Boussiotis, V.A., Freeman, G.J., Berezovskaya, A., Barber, D.L. & Nadler, L.M. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1. Science 278, 124–128 (1997).

    CAS  PubMed  Google Scholar 

  82. Eisenbraun, M.D., Tamir, A. & Miller, R.A. Altered composition of the immunological synapse in an anergic, age-dependent memory T cell subset. J. Immunol. 164, 6105–6112 (2000).

    CAS  PubMed  Google Scholar 

  83. Zhang, W. et al. Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J. Biol. Chem. 278, 23978–23983 (2003).

    CAS  PubMed  Google Scholar 

  84. Anandasabapathy, N. et al. GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18, 535–547 (2003).

    CAS  PubMed  Google Scholar 

  85. Glynne, R., Ghandour, G., Rayner, J., Mack, D.H. & Goodnow, C.C. B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays. Immunol. Rev. 176, 216–246 (2000).

    CAS  PubMed  Google Scholar 

  86. Tezuka, T. et al. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling. J. Exp. Med. 183, 675–680 (1996).

    CAS  PubMed  Google Scholar 

  87. Fournel, M., Davidson, D., Weil, R. & Veillette, A. Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes. J. Exp. Med. 183, 301–306 (1996).

    CAS  PubMed  Google Scholar 

  88. Fang, D. et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J. Biol. Chem. 276, 4872–4878 (2001).

    CAS  PubMed  Google Scholar 

  89. Sohn, H.W., Gu, H. & Pierce, S.K. Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J. Exp. Med. 197, 1511–1524 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Yasuda, T. et al. Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-γ2 activation by regulating B cell linker protein-PLC-γ2 binding. J. Exp. Med. 191, 641–650 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Fang, D. & Liu, Y.C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat. Immunol. 2, 870–875 (2001).

    CAS  PubMed  Google Scholar 

  92. Miura-Shimura, Y. et al. Cbl-mediated ubiquitinylation and negative regulation of Vav. J. Biol. Chem. 278, 38495–38504 (2003).

    CAS  PubMed  Google Scholar 

  93. Chiang, Y.J. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000).

    CAS  PubMed  Google Scholar 

  94. Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. 3, 1192–1199 (2002).

    CAS  PubMed  Google Scholar 

  95. Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).

    CAS  PubMed  Google Scholar 

  96. Yokoi, N. et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat. Genet. 31, 391–394 (2002).

    CAS  PubMed  Google Scholar 

  97. Hicke, L. A new ticket for entry into budding vesicles-ubiquitin. Cell 106, 527–530 (2001).

    CAS  PubMed  Google Scholar 

  98. Burkhard, P., Stetefeld, J. & Strelkov, S.V. Coiled coils: a highly versatile protein folding motif. Trends Cell Biol. 11, 82–88 (2001).

    CAS  PubMed  Google Scholar 

  99. Raiborg, C. et al. FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes. J. Cell. Sci. 114, 2255–2263 (2001).

    CAS  PubMed  Google Scholar 

  100. Zhong, Q. et al. Endosomal localization and function of sorting nexin 1. Proc. Natl. Acad. Sci. USA 99, 6767–6772 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bartkiewicz, M., Houghton, A. & Baron, R. Leucine zipper-mediated homodimerization of the adaptor protein c-Cbl. A role in c-Cbl's tyrosine phosphorylation and its association with epidermal growth factor receptor. J. Biol. Chem. 274, 30887–30895 (1999).

    CAS  PubMed  Google Scholar 

  102. Oved, S. & Yarden, Y. Signal transduction: molecular ticket to enter cells. Nature 416, 133–136 (2002).

    CAS  PubMed  Google Scholar 

  103. Dikic, I. CIN85/CMS family of adaptor molecules. FEBS Lett. 529, 110–115 (2002).

    CAS  PubMed  Google Scholar 

  104. Watanabe, S. et al. Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. Biochem. Biophys. Res. Commun. 278, 167–174 (2000).

    CAS  PubMed  Google Scholar 

  105. Zhong, X.P. et al. Enhanced T cell responses due to diacylglycerol kinase ξ deficiency. Nat. Immunol. 4, 882–890 (2003).

    CAS  PubMed  Google Scholar 

  106. Anderson, R.G. The caveolae membrane system. Annu. Rev. Biochem. 67, 199–225 (1998).

    CAS  PubMed  Google Scholar 

  107. Naramura, M., Kole, H.K., Hu, R.J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl. Acad. Sci. USA 95, 15547–15552 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Thien, C.B., Bowtell, D.D. & Langdon, W.Y. Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. J. Immunol. 162, 7133–7139 (1999).

    CAS  PubMed  Google Scholar 

  109. Ceresa, B.P. & Schmid, S.L. Regulation of signal transduction by endocytosis. Curr. Opin. Cell Biol. 12, 204–210 (2000).

    CAS  PubMed  Google Scholar 

  110. Di Fiore, P.P. & De Camilli, P. Endocytosis and signaling. an inseparable partnership. Cell 106, 1–4 (2001).

    CAS  PubMed  Google Scholar 

  111. Rui, L., Vinuesa, C.G., Blasioli, J. & Goodnow, C.C. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat. Immunol. 4, 594–600 (2003).

    PubMed  Google Scholar 

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Acknowledgements

We thank L. Miosge and A. Liston for proofreading the manuscript. Supported by the National Health and Medical Research Council of Australia.

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  1. Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia

    Jesse E Jun & Christopher C Goodnow

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Jun, J., Goodnow, C. Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling. Nat Immunol 4, 1057–1064 (2003). https://doi.org/10.1038/ni1001

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